One out of every six adults over the age of sixty-five consumes less than 1,000 calories/day, and in the case of older, institutionalized populations the prevalence of malnutrition increases to between twenty-three to sixty percent. It Is precisely this population that is at greatest risk for bone fractures. We hypothesize that a decline in musculoskeletal function with age is due in large part to a decline in nutrient-activated anabolic signals. This Program Project application is focused on defining the role of nutrients in age-dependent bone loss. The proposal consists of three Projects and three Core facilities. The three research projects will define the molecular mechanisms involved in nutrient modulation of bone marrow stromal cell (BMSC) differentiation and proliferation, and will determine how these mechanisms are altered with aging. The three Core facilities will add value to the program as a whole by providing essential support to the Projects while at the same time promoting aging and bone research at the Medical College of Georgia. The overall specific aims of the proposal are: (1) To determine how aging alters the response of bone-derived progenitor cells to amino acids; (2) To determine how aging alters the response of bone-and muscle-derived stem cells to nutrition-related hormones (e.g., IGF-1 and leptin); and (3) To determine how aging and nutrient-related stimuli alter the transcriptional regulation of BMSC differentiation mediated by stromal derived factor-1. Major strengths of this application include: (1) a multidisciplinary team of investigators with diverse backgrounds in molecular biology, physiology, endocrinology, and bone biology, who will bring new perspectives to solve a common problem; (2) a strong clinical-translational focus, with both M.D. clinician scientists and Ph.D. research scientists playing key roles; (3) a mixture of investigators of diverse background and training who have been working together for five years; (4) outstanding institutional support from both clinical and research departments, as well as from the MCG administration; and (5) the coordinated use of a common model of aging mice (C57BL/6) across highly integrated project components. This tight integration among the different projects makes this proposal truly synergistic and unique. Ultimately, we expect the Program Project to identify new therapeutic strategies and develop specific countermeasures for age-associated declines in musculoskeletal function.